The BMP4 signaling pathway is dysregulated in the cells of patients who have fibrodysplasia ossificans progressiva (FOP), a disabling autosomal dominant disorder of progressive heterotopic ossification and congenital limb malformations. Our previous studies suggest that FOP cells fail to properly regulate ambient concentrations of BMP4 and fail to appropriately regulate the transcription of BMP pathway target genes, including those for the BMP4 antagonists. Recent preliminary data indicate that the BMP type IA receptor (BMPRIA) is present and active at high levels on the surface of FOP cells, while the BMP type IB receptor (BMPRIB) is present at low levels. These data for FOP cells are consistent with developmental studies, which show that postnatal over-expression of BMPRIA can cause heterotopic ossification and that embryonic underexpression of BMPRIB can lead to digital malformations that closely mimic those seen in patients who have FOP. There are no mutations in the genes encoding BMP4, multiple BMP4 antagonists, pathway-specific or inhibitory Smads, or the BMP receptors in FOP patients. Taken together, these data suggest that a primary defect may exist in the BMP4 signaling pathway in FOP ceils and that BMPRIA may be constitutively active and/or unresponsive to normal signaling in FOP cells. We hypothesize that promiscuous BMP signaling in FOP cells (a) results from increased amounts of BMPRIA on the cell surface, and (b) mediates the pathophysiology of FOP. This research proposal will focus on investigations of cellular signaling events that are associated with the high steady-state levels of BMPRIA protein on the surface of FOP cells. We intend to: (1) characterize the signal transduction pathways that are activated by overabundant BMPRIA in FOP cells; (2) determine the mechanism leading to BMPRIA overabundance on the surface of FOP cells; (3) establish whether BMPRIA signaling in FOP cells is ligand-mediated or ligand independent; and (4) investigate whether over-abundance of BMPRIA on the cell surface is sufficient to mediate an "FOP phenotype". Analysis of the molecular pathology of the human BMP4 pathway in FOP will foster the long-term goal of elucidating basic mechanisms of normal and disordered bone induction in this disabling human disease. This strategy will also lead to a more rational therapeutic approach to a wide variety of disorders involving the induction of osteogenesis in humans.